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Start Preamble

AGENCY:

National Institutes of Health, Public Health Service, DHHS.

ACTION:

Notice.

SUMMARY:

The inventions listed below are owned by an agency of the U.S. Government and are available for licensing in the U.S. in accordance with 35 U.S.C. 207 to achieve expeditious commercialization of results of federally-funded research and development. Foreign patent applications are filed on selected inventions to extend market coverage for companies and may also be available for licensing.

ADDRESSES:

Licensing information and copies of the U.S. patent applications listed below may be obtained by writing to the indicated licensing contact at the Office of Technology Transfer, National Institutes of Health, 6011 Executive Boulevard, Suite 325, Rockville, Maryland 20852-3804; telephone: 301/496-7057; fax: 301/402-0220. A signed Confidential Disclosure Agreement will be required to receive copies of the patent applications.

MET is over expressed in a variety of cancers including hereditary papillary renal cell carcinoma and non-small cell lung cancer. These cell lines carry naturally-occurring Met mutations and were derived from the germline of patients with hereditary papillary renal cell carcinoma. These cell lines can be used as drug discovery research reagents.

These cell lines were described in part in Schmidt et al., “Novel mutations of the MET proto-oncogene in papillary renal carcinomas. Oncogene. (1999) 18:2343-2350 and Jeffers et al., “Activating mutations for the met tyrosine kinase receptor in human cancer.” PNAS (1997) 94:11445-11450.

In addition to licensing, the technology is available for further development through collaborative research opportunities with the inventors.Start Printed Page 61459

The NIH is pleased to offer for licensing mouse fibroblasts that stably express the C-type lectin receptors DC-SIGN and L-SIGN (CD209 and CD209L, respectively). L-SIGN and DC-SIGN both exhibit selectivity for highly mannosylated glycoproteins. DC-SIGN is also selective for certain Lewis X sugar groups. These types of interactions allow L-SIGN and DC-SIGN to interact with a wide spectrum of pathogens including HIV, hepatitis C virus, and SARS coronavirus, which appear to use L-SIGN and DC-SIGN to facilitate their replication. In addition to HIV, HCV, and SARS, pathogens such as Ebola virus, some herpes viruses, and tuberculosis interact with DC-SIGN. In contrast to primary cells expressing L-SIGN and DC-SIGN, the subject fibroblasts are resilient, adhere to coated tissue culture plates, grow rapidly and continually express high levels of their respective receptor. The subject materials could be used to study the interaction of pathogens with L-SIGN or DC-SIGN and to screen for compounds that block these interactions. Additionally, the materials could be used for the development of antibodies or compounds through rational design that interacted with L-SIGN or DC-SIGN. The NIH3T3/DC-SIGN and NIH3T3/L-SIGN cells are further described in Journal of Virology, 2002, vol. 26(12), pages 5905-5914. The subject technologies are available for licensing from the NIH through biological materials license agreements.

Murine Mast Cell Line Useful for Toxicity and Immunopotency Screens

The technology is a mouse cell line (P815) that could be useful for screening biological and chemical agents for toxicity and immunopotency. Specifically, the cell line is useful for screening for toxic effects of immunopotentiators including Mycobacterium bovis, Bacillus Calmette-Gurerin strain, zymosan, lipopolysaccharide and dextran sulfate. The cell line may also have application in screening other compounds.

The cell line may also prove useful for studies of cancer and tumor immunology as injection of mice with P815 leads to progressive tumors. The P815 tumors express cell surface antigens that could provide a model for cancer vaccine development.

Mutated Pseudomonas Exotoxins with Reduced Antigenicity

The use of Pseudomonas exotoxins (PE) for treatment of solid tumors, in particular, has been limited because of the development of neutralizing antibodies to the immunotoxin after the first administration. These antibodies develop before most protocols would call for a second administration of the immunotoxin, and therefore render further use of the immunotoxins ineffective against solid tumors in previously exposed patients.

The studies underlying this novel invention reveal that the predominant immune response of patients to PE-immunotoxins is the PE portion of the immunotoxin. This finding indicates that reducing the antigenicity of the PE molecules used for immunotoxins would reduce the overall antigenicity of the immunotoxin, and increase their utility.

Therefore, this invention relates to mutated Pseudomonas exotoxins (PE) that have reduced antigenicity compared to PEs containing the native sequence. The PEs of this invention have one or more individual mutations that reduce antibody binding to one or more epitopes of PE.

In addition to licensing, the technology is available for further development through collaborative research opportunities with the inventors.

This invention relates to materials and methods associated with polymorphic variants in two enzymes involved in folate-dependent and one-carbon metabolic pathways important in pregnancy-related complications and neural tube birth defects: MTHFD1 (5,10-methylenetrahydrofolate dehydrogenase, 5,10-methenyltetrahydrofolate cyclohydrolase, 10-formyltetrahydrofolate synthase) and methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 1-like (MTHFD1L). These enzymes are extremely important in the promotion of DNA synthesis, a process that is critical for normal placental and fetal development.

Recently, the inventors have discovered that a MTHFD1 polymorphism is also a strong maternal genetic risk factor for placental abruption, premature separation of a normally implanted placenta. This polymorphism may also be a risk factor for first and second trimester miscarriages. Diagnostic and therapeutic methods are provided in this invention involving the correlation of polymorphic variants in MTHFD1 and other genes with relative susceptibility for various pregnancy-related and other complications such as cancer, cardiovascular disease, and developmental anomalies. Both nutrient status and genetic background are independent yet interacting risk factors for impaired folate metabolism. However, the mechanisms that lead to pathology or the mechanisms whereby folate prevents these disorders are unknown. Therefore, a diagnostic and therapeutic invention of this kind would significantly improve the detection and treatment of disorders associated with folate metabolism.

For further information, see Brody et al., July 28, 2005, “A polymorphism in the MTHFD1 gene increases a mother's risk of having an unexplained second trimester pregnancy loss,” Mol. Hum. Reprod. 10.1093/molehr/gah204.

In addition to licensing, the technology is available for further development through collaborative research opportunities with the inventors.

The invention described and claimed in this patent application provides for novel vectors and viral particles which Start Printed Page 61460comprise adeno-associated virus serotype 5 (AAV5). AAV5 is a single-stranded DNA virus of either plus or minus polarity which, like other AAV serotypes (e.g., AAV4, AAV2) requires a helper virus for replication. AAV type 2 has the interesting and potentially useful ability to integrate into human chromosome 19 q 13.3-q ter. This activity is dependent on the non-structural, Rep, proteins of AAV2. The Rep proteins of AAV types 2 and 5 are dissimilar and are not able to substitute in DNA replication of the heterologous serotype.

AAV5 offers several advantages which make it attractive for use in gene therapy: 1. Increased production (10-50 fold greater than AAV2); 2. distinct integration locus when compared to AAV2; 3. Rep protein and ITR regions do not complement other AAV serotypes; and 4. appears to utilize different cell surface attachment molecules than those of AAV type 2.

In addition to licensing, the technology may be available for further development through collaborative research opportunities with the inventors.

The Use of Nitroxides in the Prophylactic and Therapeutic Treatment of Cancer Due to Genetic Defects

The invention is a method for preventing or treating cancer, especially cancers associated with defects in the p53 gene. This gene is generally considered to be a tumor-suppressor gene, and in a large percentage of malignancies including pancreatic, colon, lung, and breast, the gene is found to be inactive in the cancer. It is believed that many individuals have genetic defects in p53 predisposing them to cancer.

The invention involves the use of certain nitroxides as agents to slow the appearance or progression of tumors associated with p53 knockout. Thus, these compounds could serve as preventative agents for people predisposed to cancer, or as therapeutic agents for certain cancers. As nitroxides have already been identified as antioxidants, such agents could become part of a cancer prevention and anti-aging regimen. A new method of use for these compounds now include their use in imaging, which correlates functional information about the tumor with magnetic resonance imaging data.

Start Signature

Dated: October 13, 2005.

Steven M. Ferguson,

Director, Division of Technology Development and Transfer, Office of Technology Transfer, National Institutes of Health.